During its run, the series has been nominated for an Annie Award three times. The series was met with mostly positive reviews, and has developed a strong cult following. Merchandise based on the series has also been produced during its run, such as video games, home media releases, toys, and clothing.

The main cast of the show. From left to right: Ami, Kaz, Yumi, Jang-Keng, and Tekirai.

Hi Hi Puffy AmiYumi follows the adventures of two pop stars and best friends: Yumi Yoshimura (Grey DeLisle), a cynical, sarcastic, rough and tough punk rocker; and Ami Onuki (Janice Kawaye), a peppy, optimistic and cute schoolgirl. Both are based off the real Japanese pop duo Puffy AmiYumi, but with different appearances and exaggerated personalities. They travel around the world on their customized tour bus along with their well-intentioned yet greedy manager Kaz Harada (Keone Young). From rocking out at a concert to hanging out in their hometown of Tokyo, the duo take the world by storm with their musical talent, trend-setting style, and humor, dishing out lessons in J-pop justice and establishing the international language of "cool" along the way.

Secondary characters include: Jang-Keng (Grey DeLisle) and Tekirai (Janice Kawaye), the duo's pet cats who enjoy tormenting Kaz; Harmony (Sandy Fox), a six-year-old girl who is the self-proclaimed "Number One Fan" of Puffy AmiYumi and (later) Kaz and constantly stalks them; Eldwin Blair (Nathan Carlson), a sinister land developer who tries to tear down beloved places for his own selfish needs; King Chad (Katie Leigh), a selfish "bad boy" who is a master of the card game Stu-Pi-Doh! (a parody of Yu-Gi-Oh!); the evil Talent Suckers (Nathan Carlson; Corey Burton), a vampire rock trio from Transylvania; and Atchan (Rob Paulsen), a caricature of Vo Atsushi (lead singer of the pop band New Rote'ka) who speaks in third-person and thinks he is a superhero.

The animated Puffy AmiYumi travel all over the world in their tour bus. While appearing the same size as a regular bus on the outside, it appears to have enough internal space to house the girls' rooms (including full-sized beds), Kaz's room, their equipment, televisions, and computers, among other things. In the episode "Domo", Kaz refers to an upstairs area. It also seems capable of running on autopilot, as Kaz, Ami, and Yumi are sometimes sitting in the rear cabin of the bus while traveling. Occasionally, the rear door has been opened to receive packages delivered by a boy on a scooter.

During the first season, the show included live-action clips of the real Ami and Yumi making childish commentary (in English and non-subtitled Japanese) at the beginning and end of each episode. They only performed short clips at the beginning of the show during the second and third seasons. Starting with the second season, the duo was sometimes shown holding title cards introducing the cartoon segments. At the end of the episode "Sitcomi Yumi", Ami and Yumi watched television and saw the animated Kaz with the real Ami and Yumi. All of the live-action clips were produced by Freegate, Ltd.

The real PUFFY performs the cartoon's theme song (which is also in Japanese, German, Spanish, and Portuguese in the respective regions), and many episodes feature one or more of the duo's songs playing in the background, along with music by Andy Sturmer.

Though the characters speak English, the script intersperses their vernacular with Japanese speech, especially when the characters react to events that they find to be surprising. Calling out "Tasukete!" instead of "Help!" is commonly used.

According to Register, the target audience of the show is boys and girls from 6–11 years old.[1] However, it also has a cult following of teen and adult fans of the real-life Ami Onuki and Yumi Yoshimura who make up the Japanese pop duo Puffy AmiYumi. Register, who was a fan of the band, wished to spread its fame to other parts of the world and thus created the series.[2]

The series features the adventures of animated versions of the duo, who have been immensely popular in Japan since making their debut in 1996. The group now has its own U.S. albums, including a 2004 companion album to this program, and was known to viewers of Cartoon Network in the USA for performing the theme to the Teen Titans animated series. During production of the series, DeLisle learned some Japanese from Kawaye and Young, both of whom speak the language fluently.

Sam Register originally pitched the idea of Puffy AmiYumi having their own television series on Cartoon Network and afterwards Renegade Animation developed a test short on April 22, 2003 in hopes of making the channel greenlight the show's production. Renegade Animation originally, at first, created other Cartoon Network pilots before Hi Hi Puffy AmiYumi; two of which feature Captain Sturdy; one in 2001, entitled "Back in Action", and the other in 2003, entitled "The Originals", but they were ultimately rejected, and Renegade Animation then started working on Hi Hi Puffy AmiYumi starting with its pilot on April 22, 2003. The pilot was not broadcast, but was initially successful, and got the green-light from Cartoon Network. Finally, it was shown in non-full version as a preview on Cartoon Network DVDs and VHS tapes.[7] The entire pilot was found by series' director, Darrell Van Citters, and was uploaded to Vimeo on April 5, 2018.[8][9]

The series was officially announced at Cartoon Network's upfront on February 26, 2004. It was originally planned to premiere in December 2004,[10] but was later pushed back to November 19.[11]

On October 2, 2006, the show's crew announced on their blog (puffycrew.blogspot.com) that Cartoon Network had cancelled Hi Hi Puffy AmiYumi after three seasons and 39 episodes due to Sam Register leaving the channel. Afterwards, the network removed all mention of the series from its website.

Cartoon Network didn't acknowledge the series again until 2012, when Ami and Yumi appeared on the channel's 20th anniversary poster.[12]

Hi Hi Puffy AmiYumi premiered in the United States on Cartoon Network on November 19, 2004.[11] After ending on June 27, 2006, the show continued to rerun until December 22, 2006, where it aired in reruns normally, and occasionally, would be one of the few non-Cartoon Cartoons to air in reruns on The Cartoon Cartoon Show before being removed from the network's schedule.[13]

Since Cartoon Network is available worldwide, the show has been dubbed into multiple languages and aired on Cartoon Network worldwide. In Canada, the series premiered on YTV on September 5, 2005.[14] In Japan, the show began airing on Cartoon Network in English with Japanese subtitles in 2005. A dubbed version began airing on TV Tokyo's Oha Suta block on October 6, 2005, and started to air on January 8, 2006 on Cartoon Network Japan.

In Australia, the show premiered on the April 3, 2005.[15] It stopped airing on Cartoon Network Australia in November 2008. The third season was never shown there. From August to November 2009, the Australian channel GO! showed the last season instead and was abandoned in January 2010.[citation needed]

Hi Hi Puffy AmiYumi debuted on Cartoon Network on November 19, 2004 at 7:30 PM ET/PT with two half-hour episodes. The show charted double-digit increases with Girls 6–11 in ratings and delivery for Cartoon Network's Fridays programming block.[16] During the following week, the show became the network's top-rated hit for kids 6–11. It also increased Cartoon Network's audience among that age group by 49% over the previous year.[17]

A "falloon" (a float with balloon elements) of Puffy AmiYumi's cartoon tour bus (complete with the supporting characters in puppet form), the cartoon version of Puffy AmiYumi as a balloon, and the real PUFFY appeared in the Macy's Thanksgiving Day Parade in 2005.[19] A video of this Macy Parade Float in Chicago can be viewed on SUMO.tv[permanent dead link].

A line of toys intended for girls was produced by Mattel (makers of the popular Barbie doll and Hot Wheels cars) and released for the 2005 Christmas season.

Two DVDs, Let's Go! and Rock Forever, featuring various episodes of the show, were released on November 29, 2005.

The American costume company Rubie's produced a line of Hi Hi Puffy AmiYumi costumes and accessories for girls for Halloween 2006.[20][21]